Connexin 43 in cardiomyocyte mitochondria and its increase by ischemic preconditioning

Boengler, Kerstin; Dodoni, Giuliano; Rodríguez‐Sinovas, Antonio; Cabestrero, Alberto; Ruiz‐Meana, Marisol; Gres, Petra; Konietzka, Ina; López‐Iglesias, Carmen; Garcı́a-Dorado, David; Lisa, Fabio Di; Heusch, Gerd; Schulz, Rainer

doi:10.1016/j.cardiores.2005.04.014

Cited by 288 publications

(256 citation statements)

References 36 publications

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“…Moreover, SB216763 had only a minimal effect on mitoK ATP channel activity of mitoplasts from conditional Cx43-deficient mice [4-hydroxytamoxifen (4-OHT)-treated Cx43 Cre-ER(T)/fl mice] ( Fig. 1 B and F and Table 1), which contain a residual 5-10% cardiac Cx43 (11), supporting the notion that GSK3 transfers protective signaling via Cx43 onto mitoK ATP channels.…”

Section: Resultsmentioning

confidence: 55%

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RETRACTED: Glycogen synthase kinase 3β transfers cytoprotective signaling through connexin 43 onto mitochondrial ATP-sensitive K ⁺ channels

Rottlaender

Boengler²,

Wolny³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Section: Resultsmentioning

confidence: 55%

“…More complete ablation of Cx43 (residual 5-10% Cx43) was induced in adult Cx43 Cre-ER(T)/fl mice by i.p. injection of 3 mg of 4-OHT once per day on 5 d consecutively as previously described (11). These animals were killed at day 12 after the first injection.…”

Section: Methodsmentioning

confidence: 99%

RETRACTED: Glycogen synthase kinase 3β transfers cytoprotective signaling through connexin 43 onto mitochondrial ATP-sensitive K ⁺ channels

Rottlaender

Boengler²,

Wolny³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…The production of ROS is one of the byproducts of mitochondrial respiration, and mitochondrias have frequently been considered as the main source of cellular- derived ROS (25). Mitochondrial Cx43 has been shown to play a role in mediating the cardioprotective effect of ischemic preconditioning through modification of the mitochondrial content and membrane potential (26). Analysis of O 2 − generated by mitochondrial activity showed that, similarly to overall intracellular ROS levels, mitochondrial-derived superoxide levels were increased in 5-FU-treated H-Cx43-deficient HSCs compared with WT HSCs (Fig.…”

Section: To Clarify Whethermentioning

confidence: 99%

Connexin-43 prevents hematopoietic stem cell senescence through transfer of reactive oxygen species to bone marrow stromal cells

Ishikawa

González‐Nieto

Ghiaur

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

142

105

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Hematopoietic stem cell (HSC) aging has become a concern in chemotherapy of older patients. Humoral and paracrine signals from the bone marrow (BM) hematopoietic microenvironment (HM) control HSC activity during regenerative hematopoiesis. Connexin-43 (Cx43), a connexin constituent of gap junctions (GJs) is expressed in HSCs, down-regulated during differentiation, and postulated to be a self-renewal gene. Our studies, however, reveal that hematopoietic-specific Cx43 deficiency does not result in significant long-term competitive repopulation deficiency. Instead, hematopoietic Cx43 (H-Cx43) deficiency delays hematopoietic recovery after myeloablation with 5-fluorouracil (5-FU). 5-FU-treated H-Cx43-deficient HSC and progenitors (HSC/P) cells display decreased survival and fail to enter the cell cycle to proliferate. Cell cycle quiescence is associated with down-regulation of cyclin D1, up-regulation of the cyclin-dependent kinase inhibitors, p21 cip1. and p16 INK4a , and Forkhead transcriptional factor 1 (Foxo1), and activation of p38 mitogen-activated protein kinase (MAPK), indicating that H-Cx43-deficient HSCs are prone to senescence. The mechanism of increased senescence in H-Cx43-deficient HSC/P cells depends on their inability to transfer reactive oxygen species (ROS) to the HM, leading to accumulation of ROS within HSCs. In vivo antioxidant administration prevents the defective hematopoietic regeneration, as well as exogenous expression of Cx43 in HSC/P cells. Furthermore, ROS transfer from HSC/P cells to BM stromal cells is also rescued by reexpression of Cx43 in HSC/P. Finally, the deficiency of Cx43 in the HM phenocopies the hematopoietic defect in vivo. These results indicate that Cx43 exerts a protective role and regulates the HSC/P ROS content through ROS transfer to the HM, resulting in HSC protection during stress hematopoietic regeneration.

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“…In cardiomyocytes, Cx43 can also localize within mitochondrial membranes, where it has been implicated in enhanced ischemic preconditioning response. Accordingly, some authors reported that during stress conditions, as occurs in myocardial ischemia, the levels of mitochondrial Cx43 raise, which could contribute to keep the mitochondrial permeability transition pore (MPTP) in a closed state, delaying the release of apoptotic proteins and cytochrome c, thus reducing ischemia/reperfusion (I/R) injury (7,8).…”

mentioning

confidence: 99%

Interacting Network of the Gap Junction (GJ) Protein Connexin43 (Cx43) is Modulated by Ischemia and Reperfusion in the Heart*

Martins‐Marques

Anjo

Pereira

et al. 2015

Molecular & Cellular Proteomics

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The coordinated and synchronized cardiac muscle contraction relies on an efficient gap junction-mediated intercellular communication (GJIC) between cardiomyocytes, which involves the rapid anisotropic impulse propagation through connexin (Cx)-containing channels, namely of Cx43, the most abundant Cx in the heart. Expectedly, disturbing mechanisms that affect channel activity, localization and turnover of Cx43 have been implicated in several cardiomyopathies, such as myocardial ischemia. Besides gap junction-mediated intercellular communication, Cx43 has been associated with channel-independent functions, including modulation of cell adhesion, differentiation, proliferation and gene transcription. It has been suggested that the role played by Cx43 is dictated by the nature of the proteins that interact with Cx43. Therefore, the characterization of the Cx43-interacting network and its dynamics is vital to understand not only the molecular mechanisms underlying pathological malfunction of gap junction-mediated intercellular communication, but also to unveil novel and unanticipated biological functions of Cx43. In the present report, we applied a quantitative SWATH-MS approach to characterize the Cx43 interactome in rat hearts subjected to ischemia and ischemiareperfusion. Our results demonstrate that, in the heart, Cx43 interacts with proteins related with various biological processes such as metabolism, signaling and trafficking.

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Connexin 43 in cardiomyocyte mitochondria and its increase by ischemic preconditioning

Abstract: These data demonstrate that Cx43 is localized at cardiomyocyte mitochondria and that IP enhances such mitochondrial localization.

Cited by 288 publications

References 36 publications

RETRACTED: Glycogen synthase kinase 3β transfers cytoprotective signaling through connexin 43 onto mitochondrial ATP-sensitive K ⁺ channels

RETRACTED: Glycogen synthase kinase 3β transfers cytoprotective signaling through connexin 43 onto mitochondrial ATP-sensitive K ⁺ channels

Connexin-43 prevents hematopoietic stem cell senescence through transfer of reactive oxygen species to bone marrow stromal cells

Interacting Network of the Gap Junction (GJ) Protein Connexin43 (Cx43) is Modulated by Ischemia and Reperfusion in the Heart*

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Connexin 43 in cardiomyocyte mitochondria and its increase by ischemic preconditioning

Abstract: These data demonstrate that Cx43 is localized at cardiomyocyte mitochondria and that IP enhances such mitochondrial localization.

Cited by 288 publications

References 36 publications

RETRACTED: Glycogen synthase kinase 3β transfers cytoprotective signaling through connexin 43 onto mitochondrial ATP-sensitive K + channels

RETRACTED: Glycogen synthase kinase 3β transfers cytoprotective signaling through connexin 43 onto mitochondrial ATP-sensitive K + channels

Connexin-43 prevents hematopoietic stem cell senescence through transfer of reactive oxygen species to bone marrow stromal cells

Interacting Network of the Gap Junction (GJ) Protein Connexin43 (Cx43) is Modulated by Ischemia and Reperfusion in the Heart*

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RETRACTED: Glycogen synthase kinase 3β transfers cytoprotective signaling through connexin 43 onto mitochondrial ATP-sensitive K ⁺ channels

RETRACTED: Glycogen synthase kinase 3β transfers cytoprotective signaling through connexin 43 onto mitochondrial ATP-sensitive K ⁺ channels